Allosteric modulation of SHP2: Quest from known to unknown

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• Src homology-2 domain-containing protein tyrosine phosphatase-2 (SHP2) is a key regulator of the cell cycle.
• Activating mutations in SHP2 are implicated in various cancers, positioning it as a critical therapeutic target.
• The conserved, positively charged active site of SHP2 presents challenges for developing high-affinity, cell-permeable orthosteric inhibitors, rendering it an 'undruggable' target.

Purpose of the Study:

• To elucidate the oncogenic mechanisms driven by SHP2.
• To review and summarize the methodologies employed in the discovery of SHP2 allosteric inhibitors.
• To provide insights and strategies for the design and optimization of novel SHP2 allosteric inhibitors.

Main Methods:

• Literature review focusing on SHP2's role in cancer.
• Analysis of studies detailing the discovery and characterization of SHP2 allosteric inhibitors.
• Exploration of allosteric regulation as a therapeutic strategy.

Main Results:

• SHP2's critical role in oncogenesis is confirmed.
• Allosteric inhibition emerges as a viable alternative to overcome the limitations of targeting SHP2's active site.
• The review consolidates various discovery approaches for SHP2 allosteric inhibitors.

Conclusions:

• Allosteric inhibition represents a more selective and safer approach for targeting SHP2 compared to orthosteric inhibitors.
• Understanding SHP2's allosteric regulation opens new avenues for cancer therapy.
• This review offers a strategic framework for advancing SHP2 allosteric inhibitor development.